ACETAMINOPHEN | TERIS agent - 1017

 

TERIS Agent Number: 1017 Bibliographic Search Date: 01/2022
Agent Name: ACETAMINOPHEN    

 

Acetaminophen is an oral analgesic and antipyretic agent.


Magnitude of Teratogenic Risk to Child Born After Exposure During Gestation:
 
CONGENITAL ANOMALIES: UNLIKELY

 

NEURODEVELOPMENTAL OUTCOMES: MINIMAL


Quality and Quantity of Data on Which Risk Estimate is Based:
 
CONGENITAL ANOMALIES: FAIR

 

NEURODEVELOPMENTAL OUTCOMES: FAIR


Comments:   

1) THERAPEUTIC DOSES OF ACETAMINOPHEN DURING THE FIRST TRIMESTER OF PREGNANCY ARE UNLIKELY TO POSE A SUBSTANTIAL TERATOGENIC RISK FOR MALFORMATIONS, BUT THE DATA ARE INSUFFICIENT TO SAY THERE IS NO RISK.

 

2) THIS ASSESSMENT IS FOR USUAL THERAPEUTIC DOSES OF ACETAMINOPHEN; THE TERATOGENIC RISK MAY BE GREATER WITH A MATERNALLY TOXIC DOSE EARLY IN PREGNANCY.

 

3) THE TERATOGENIC RISK OF ACETAMINOPHEN MAY BE INCREASED WITH CHRONIC MATERNAL USE AS COMPARED TO SHORT-TERM USE AT THERAPEUTIC DOSES.

 

4) THERE IS A RISK OF SERIOUS FETAL LIVER OR RENAL TOXICITY WHEN THE MOTHER TAKES A TOXIC OVERDOSE OF ACETAMINOPHEN LATE IN PREGNANCY (SEE BELOW).

 

5) AN ASSOCIATION OF MATERNAL ACETAMINOPHEN USE DURING PREGNANCY WITH THE OCCURRENCE OF ASTHMA IN THE CHILD HAS BEEN REPORTED (SEE BELOW). IF THIS ASSOCIATION IS REAL, IT MAY REFLECT THE PRESENCE OF OTHER FACTORS THAT ARE ASSOCIATED WITH MATERNAL ACETAMINOPHEN USE AND WITH THE DEVELOPMENT OF ASTHMA IN A CHILD RATHER THAN A DIRECT EFFECT OF THE ACETAMINOPHEN TREATMENT.

 

6) MATERNAL USE OF ACETAMINOPHEN JUST BEFORE DELIVERY MAY BE ASSOCIATED WITH ABNORMALITIES OF NEONATAL CARDIOVASCULAR ADAPTATION (SEE BELOW).

 

7) STUDIES ON MATERNAL ACETAMINOPHEN USE IN PREGNANCY AND NEURODEVELOPMENTAL OUTCOMES IN CHILDREN SUFFER FROM SIGNIFICANT BIASES AND ARE DIFFICULT TO INTERPRET (SEE BELOW).


Summary of Teratology Studies:

MAJOR CONGENITAL ANOMALIES

 

Several cohort studies have found marginal evidence supporting an association of maternal use of acetaminophen during the first and second trimesters of pregnancy with congenital cryptorchidism. This includes 22,449 exposed male children in the Danish National Birth Cohort (hazard ratio=1.33, 95% confidence interval 1.00-1.77) (Jensen et al., 2010, 2011) and 3184 boys enrolled in a Dutch study (odds ratio=1.85, 95% confidence interval 1.02-3.37) (Snijder et al., 2012). A dose-dependent relationship was found between the occurrence of cryptorchidism and the frequency of maternal acetaminophen use during the first or second trimester of pregnancy in an independent study of 491 boys in Denmark and Finland (Kristensen et al., 2011).

 

The overall prevalence of congenital anomalies was no greater than expected among 26,424 children whose mothers used acetaminophen during the first trimester of pregnancy in the Danish National Birth Cohort (Rebordosa et al., 2008). However, an association was seen with congenital anomalies of the ear, face, or neck in this study (hazard ratio=1.82, 95% confidence interval 1.11-2.99). Congenital anomalies were observed 2.3 times more often than expected (95% confidence interval 1.0-5.4 times) in a Danish study of 55 infants whose mothers were given prescriptions for daily acetaminophen treatment during the first trimester of pregnancy or in the month before conception (Thulstrup et al., 1999). The distribution of congenital anomalies in this study did not indicate a causal link with acetaminophen.

 

No association with maternal acetaminophen use and congenital anomalies was found among the infants of 9989 mothers who used acetaminophen during the first trimester of pregnancy in multiple cohort studies (Jick et al., 1981; Aselton et al., 1985; Rosa et al., 1993).

 

The frequency of maternal use of acetaminophen during the first trimester or anytime during pregnancy was no greater than expected among children with congenital anomalies (11,610 cases), microcephaly (166 cases), cardiac (466 cases) and renal (192 cases) anomalies, neural tube defects (538 cases), and gastroschisis (286 cases) in multiple case-control studies (Zierler & Rothman, 1985; Shaw et al., 1998; Abe et al., 2003; Cleves et al., 2004; Feldkamp et al., 2010; Kerr et al., 2019; Weber et al., 2019).

 

However, marginal positive findings have been reported in some case-control studies. Maternal first-trimester acetaminophen use was more frequent than expected among infants with amniotic bands involving only the limbs (53 cases, odds ratio=2.1, 95% confidence interval 1.1-3.9) or involving the face or neural tube, with or without limb involvement (20 cases, odds ratio=3.4, 95% confidence interval 1.1-10.3) (Werler et al., 2003). An association with maternal use of acetaminophen during embryogenesis was observed among 601 infants with primary cleft palate (odds ratio=3.7, 95% confidence interval 1.1-12.0) but not among 1374 infants with isolated cleft lip with or without cleft palate in the Hungarian Case-Control Surveillance of Congenital Anomalies (Puho et al., 2007). Overall acetaminophen use during pregnancy has also been associated with a slightly increased risk of gastroschisis (216 cases, odds ratio=1.5, 95% confidence interval 1.1-2.2) (Werler et al., 2002).

 

The frequency of maternal use of acetaminophen during embryogenesis was greater than expected among infants with tetralogy of Fallot (59 cases, adjusted odds ratio=1.6, 95% confidence interval 1.1-2.3) (Marsh et al., 2014). This result may be due to chance because of the large number of phenotypic comparisons made.

 

ADVERSE PREGNANCY AND NEONATAL OUTCOMES

 

The use of acetaminophen during pregnancy was not associated with adverse perinatal outcomes, including preterm birth, low birth weight or low weight for gestational age in a meta-analysis of several large cohort and case-control studies (Castro et al., 2022). Furthermore, no increased risk of preterm birth or low birth weight among women with autoimmune disorders who used acetaminophen in pregnancy was reported in the MotherToBaby prospective cohort study (Killion et al., 2021). In other cohort and case-control studies, the prevalences of stillbirth, miscarriage, or amniotic bands were not increased among 80,652 women who used acetaminophen anytime during pregnancy (Pastore et al., 1999; Li et al., 2003; Rebordosa et al., 2009; Feldkamp et al., 2010; Smarr et al., 2019).

 

A 2019 observational study from the prospective German Embryotox cohort found that third trimester acetaminophen use was not associated with ductus arteriosus closure or fetal renal impairment in infants born to 604 women who used acetaminophen during the third trimester (Dathe et al., 2019). Although a case series analysis of 25 cases of fetal ductus arteriosus constriction or closure suggested that an association with maternal acetaminophen use during pregnancy was likely (Allegaert et al., 2019), the data were limited by inadequate descriptions of used analgesic medications and lacked detail in some cases on dose and timing of prenatal acetaminophen use.

 

Hepatoxicity and nephrotoxicity occur as complications of acetaminophen overdosage in adults. Similar effects have been observed among infants born to women who took large therapeutic or toxic doses of acetaminophen late in pregnancy (Aw et al., 1999; Wilkes et al., 2005). Fetal distress and fetal death have occurred in pregnant women who took hepatotoxic overdoses of acetaminophen in the second or third trimester (Rosevear & Hope, 1989; Thornton & Minns, 2012; Franko et al., 2013).

 

LONG-TERM HEALTH OUTCOMES

 

There is controversy over whether the limited positive associations that have been observed between maternal use of acetaminophen during pregnancy and asthma in the child reflect a causal relationship or result from incompletely controlled confounding due to maternal asthma or infections (Migliore et al., 2015).

 

Acetaminophen use during pregnancy has been associated with an increased risk of asthma/wheeze in children whose mothers used acetaminophen during pregnancy in multiple prospective and retrospective cohort studies (Sordillo et al., 2015; Liu et al., 2016; Magnus et al., 2016; Shaheen et al., 2019; Liew et al., 2021) but this association is not found in all investigations (Piler et al., 2018).

 

An elevated risk of childhood asthma was associated with gestational acetaminophen exposure in a meta-analysis that included 1,043,109 individuals (odds ratio=1.19, 95% confidence interval 1.12-1.27; p<0.00001) (Fan et al., 2017). This relationship remained significant when the sample was restricted to children with first trimester acetaminophen exposure only (odds ratio=1.21, 95% confidence interval 1.14-1.28). A 2021 analysis of six systematic reviews and three additional studies reported a maximum of a 1.5-fold increase in odds of asthma developing in acetaminophen exposed children (Singh et al., 2021).

 

In a record-linkage study from Taiwan, an increased prevalence of maternal acetaminophen use in pregnancy was reported among 2529 mothers of children affected with atopic dermatitis compared to mothers of unaffected children (Li et al., 2021). The associations were dose-dependent and strongest when acetaminophen exposure occurred in the first or second trimester or in all trimesters of pregnancy.

 

NEURODEVELOPMENTAL OUTCOMES

 

A growing number of studies and reviews have raised considerable public attention reporting associations of prenatal acetaminophen use and adverse childhood neurodevelopmental outcomes (Bauer et al., 2021). However, some investigators cautioned against an inference of causality based on inadequate evidence from the reported data (Liew & Ernst, 2021; Alwan et al., 2022; Damkier et al., 2022). It is important to note that the studies reported below suffer from serious biases, including variability in selection and adjustment of various potential confounders as well as issues with quality and validity of neurodevelopmental outcome definitions.

 

An increased risk of attention-deficit/hyperactivity disorder in children whose mothers used acetaminophen during pregnancy has been reported in numerous epidemiology studies (Liew et al., 2014; Thompson et al., 2014; Ystrom et al., 2017; Chen et al., 2019; Baker et al., 2020) and a 2019 meta-analysis of 244,940 mother-child dyads (pooled adjusted risk ratio=1.25, 95% confidence interval 1.17-1.34) (Gou et al., 2019). Third trimester exposure appeared to be related to a higher prevalence of attention-deficit/hyperactivity disorder childhood diagnoses. Several cohort studies have also reported associations of maternal acetaminophen use during pregnancy and increased odds of having a child on the autism spectrum (Avella-Garcia et al., 2016; Liew et al., 2016b; Ji et al., 2020). A meta-analysis of data from 132,738 mother-child pairs identified a modest increase for autism spectrum diagnoses in children born to mothers who used acetaminophen during pregnancy (risk ratio=1.19, 95% confidence interval 1.14-1.25) (Masarwa et al., 2018). The authors noted that this finding was likely influenced by uncontrolled confounding variables. Furthermore, a broad range of other cognitive and behavioral outcomes including conduct problems, reduced IQ scores, deficits in executive function, and oppositional defiant disorder symptoms have been associated with maternal use of acetaminophen during pregnancy (Liew et al., 2016a, c; Stergiakouli et al., 2016; Ruisch et al., 2018; Golding et al., 2020; Rifas-Shiman et al., 2020; Tronnes et al., 2020; Inoue et al., 2021). Delays in early communication and language development have also been documented in children prenatally exposed to acetaminophen (Vlenterie et al., 2016; Bornehag et al., 2018).

 

In contrast, results from several large population-based cohort studies demonstrated either no effect of acetaminophen on cognitive/behavioral performance or inconclusive results (Brandlistuen et al., 2013; Laue et al., 2019; Bertoldi et al., 2020; Tovo-Rodrigues et al., 2020).

 

OTHER NEURODEVELOPMENTAL OUTCOMES

 

An increased risk of cerebral palsy was found among children born to 90,952 mothers who used acetaminophen during pregnancy in the Danish National Birth Cohort and the Norwegian Mother and Child Cohort Study, but the association was of borderline statistical significance (adjusted odds ratio=1.3, 95% confidence interval 1.0-1.7) (Petersen et al., 2018).

 

ANIMAL TERATOLOGY STUDIES

 

Studies in pregnant mice and rats have shown no evidence of a teratogenic effect of acetaminophen treatment in doses similar to those used clinically in humans (Scialli et al., 2010). Similarly, mouse studies using human therapeutic levels of treatment found no adverse effect of maternal acetaminophen treatment on litter size (Iacob et al., 2019), offspring hyperkinetic behavior (Saad et al., 2016), and risk of allergic airway disease (Lee et al., 2015). In two independent studies however, reduced fetal weights and increased airway inflammation were observed in animals with a history of prenatal exposure (Karimi et al., 2015; Thiele et al., 2015). Alterations of several behavioral endpoints were observed among the offspring of pregnant rats treated with acetaminophen at a dose falling within the human therapeutic range, in an experimental study that suggests acetaminophen may be a developmental neurotoxicant (Klein et al., 2020).

Selected References:
(Each paper is classified as a review [R], human case report [C], human epidemiological study [E], human clinical series [S], animal study [A], or other [O].)

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Allegaert K, Mian P, Lapillonne A, van den Anker JN: Maternal paracetamol intake and fetal ductus arteriosus constriction or closure: a case series analysis. Br J Clin Pharmacol 85(1):245-251, 2019. [S]

 

Alwan S, Conover EA, Harris-Sagaribay L, Lamm SH, Lavigne SV, Lusskin SI, Obican SG, Romeo AN, Scialli AR, Wisner KL: Paracetamol use in pregnancy--caution over causal inference from available data. Nat Rev Endocrinol 18(3):190, 2022. [O]

 

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Avella-Garcia CB, Julvez J, Fortuny J, Rebordosa C, Garcia-Esteban R, Galan IR, Tardon A, Rodríguez-Bernal CL, Iniguez C, Andiarena A, Santa-Marina L, Sunyer J: Acetaminophen use in pregnancy and neurodevelopment: attention function and autism spectrum symptoms. Int J Epidemiol 45(6):1987-1996, 2016. [E]

 

Aw MM, Dhawan A, Baker AJ, Mieli-Vergani G: Neonatal paracetamol poisoning. Arch Dis Child Fetal Neonatal Ed 81(1):F78, 1999. [C]

 

Baker BH, Lugo-Candelas C, Wu H, Laue HE, Boivin A, Gillet V, Aw N, Rahman T, Lepage JF, Whittingstall K, Bellenger J-P, Posner J, Takser L, Baccarelli AA: Association of prenatal acetaminophen exposure measured in meconium with risk of attention-deficit/hyperactivity disorder mediated by frontoparietal network brain connectivity. JAMA Pediatr 174(11):1073-1081, 2020. [E]

 

Bauer AZ, Swan SH, Kriebel D, Liew Z, Taylor HS, Bornehag C-G, Andrade AM, Olsen J, Jensen RH, Mitchell RT, Skakkebaek NE, Jegou B, Kristensen DM: Paracetamol use during pregnancy--a call for precautionary action. Nat Rev Endocrinol 17(12):757-766, 2021. [R]

 

Bertoldi AD, Rifas-Shiman SL, Boing AC, da Silva Dal Pizzol T, Miranda VIA, Silveira MPT, Freitas Silveira M, Domingues MR, Santos IS, Bassani DG, Tovo-Rodrigues L, Oken E: Associations of acetaminophen use during pregnancy and the first year of life with neurodevelopment in early childhood. Paediatr Perinat Epidemiol 34(3):267-277, 2020. [E]

 

Bornehag C-G, Reichenberg A, Hallerback MU, Wikstrom S, Koch HM, Jonsson BA, Swan SH: Prenatal exposure to acetaminophen and children's language development at 30 months. Eur Psychiatry 51:98-103, 2018. [E]

 

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Castro CT, Gama RS, Pereira M, Oliveira MG, Dal-Pizzol TS, Barreto ML, Santos DB: Effect of acetaminophen use during pregnancy on adverse pregnancy outcomes: a systematic review and meta-analysis. Expert Opin Drug Saf 21(2):241-251, 2022. [R]

 

Chen M-H, Pan T-L, Wang P-W, Hsu J-W, Huang K-L, Su T-P, Li C-T, Lin W-C, Tsai S-J, Chen T-J, Bai Y-M: Prenatal exposure to acetaminophen and the risk of attention-deficit/hyperactivity disorder: a nationwide study in Taiwan. J Clin Psychiatry 80(5):18m12612, 2019. [E]

 

Cleves MA, Savell VH Jr, Raj S, Zhao W, Correa A, Werler MM, Hobbs CA: Maternal use of acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs), and muscular ventricular septal defects. Birth Defects Res Part A Clin Mol Teratol 70(3):107-113, 2004. [E]

 

Damkier P, Cleary B, Weber-Schoendorfer C, Shechtman S, Cassina M, Panchaud A, Diav-Cirtin O: Handle with care--interpretation, synthesis and dissemination of data on paracetamol in pregnancy. Nat Rev Endocrinol 18(3):191, 2022. [O]

 

Dathe K, Frank J, Padberg S, Hultzsch S, Meixner K, Beck E, Meister R, Schaefer C: Negligible risk of prenatal ductus arteriosus closure or fetal renal impairment after third-trimester paracetamol use: evaluation of the German Embryotox cohort. BJOG 126(13):1560-1567, 2019. [E]

 

Fan G, Wang B, Liu C, Li D: Prenatal paracetamol use and asthma in childhood: a systematic review and meta-analysis. Allergol Immunopathol 45(6):528-533, 2017. [R]

 

Feldkamp ML, Meyer RE, Krikov S, Botto LD: Acetaminophen use in pregnancy and risk of birth defects: findings from the National Birth Defects Prevention Study. Obstet Gynecol 115(1):109-115, 2010. [E]

 

Franko KR, Mekeel KL, Woelkers D, Khanna A, Hemming AW: Accidental acetaminophen overdose results in liver transplant during second trimester of pregnancy: a case report. Transplant Proc 45(5):2063-2065, 2013. [C]

 

Golding J, Gregory S, Clark R, Ellis G, Iles-Caven Y, Northstone K: Associations between paracetamol (acetaminophen) intake between 18 and 32 weeks gestation and neurocognitive outcomes in the child: a longitudinal cohort study. Paediatr Perinat Epidemiol 34(3):257-266, 2020. [E]

 

Gou X, Wang Y, Tang Y, Qu Y, Tang J, Shi J, Xiao D, Mu D: Association of maternal prenatal acetaminophen use with the risk of attention deficit/hyperactivity disorder in offspring: a meta-analysis. Aust N Z J Psychiatry 53(3):195-206, 2019. [R]

 

Iacob RE, Iacob D, Moleriu RD, Tit DM, Bungau S, Otrisal P, Aleya S, Judea-Pusta C, Cioca G, Bratu OG, Aleya L, Petre I: Consequences of analgesics use in early pregnancy: results of tests on mice. Sci Total Environ 691:1059-1064, 2019. [A]

 

Inoue K, Ritz B, Ernst A, Tseng WL, Yuan Y, Meng Q, Ramlau-Hansen CH, Strandberg-Larsen K, Arah OA, Obel C, Li J, Olsen J, Liew Z: Behavioral problems at age 11 years after prenatal and postnatal exposure to acetaminophen: parent-reported and self-reported outcomes. Am J Epidemiol 190(6):1009-1020, 2021. [E]

 

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Jensen MS, Rebordosa C, Thulstrup AM, Toft G, Sorensen HT, Bonde JP, Henriksen TB, Olsen J: Maternal use of acetaminophen, ibuprofen, and acetylsalicylic acid during pregnancy and risk of cryptorchidism. Epidemiology 21(6):779-785, 2010. [E]

 

Ji Y, Azuine RE, Zhang Y, Hou W, Hong X, Wang G, Riley A, Pearson C, Zuckerman B, Wang X: Association of cord plasma biomarkers of in utero acetaminophen exposure with risk of attention-deficit/hyperactivity disorder and autism spectrum disorder in childhood. JAMA Psychiatry 77(2):180-189, 2020. [E]

 

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Killion JA, Chambers C, Smith CJF, Bandoli G: Prenatal acetaminophen use in women with autoimmune disorders and adverse pregnancy and birth outcomes. Rheumatology 2021 Aug 3 (published online ahead of print). [E]

 

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Li C-Y, Dai Y-X, Chang Y-T, Bai Y-M, Tsai S-J, Chen T-J, Chen M-H: Prenatal exposure to acetaminophen increases the risk of atopic dermatitis in children: a nationwide nested case-control study in Taiwan. Pediatr Allergy Immunol 32(5):1080-1088, 2021. [E]

 

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